Trial Review

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NIVORAD - A randomised phase 2 trial of nivolumab and stereotactic ablative body radiotherapy in advanced non-small cell lung cancer, progressing after first or second line chemotherapy.

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Scientific title

NIVORAD - A randomised phase 2 trial of nivolumab and stereotactic ablative body radiotherapy in advanced non-small cell lung cancer, progressing after first or second line chemotherapy.

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Secondary ID [1]2885180

Nil

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Universal Trial Number (UTN)

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Trial acronym

NIVORAD

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Linked study record

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Health condition

Health condition(s) or problem(s) studied:

Advanced non-small cell lung cancer, progressing after first of second line chemotherapy2975950

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Condition category

Condition code

Cancer29779229779200

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Lung - Non small cell

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Intervention/exposure

Study type

Interventional

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Description of intervention(s) / exposure

Nivolumab 240mg every 2 weeks plus Stereotactic Ablative Body Radiotherapy (SABR). Nivolumab (240mg) will be administered as an intravenous infusion every 2 weeks until disease progression or prohibitive toxicity. SABR (18-20 Gy) will be administered to a single lesion between days 8 - 14 of cycle 1 of Nivolumab. The specific day of SABR will be at clinical discretion of the treating radiation oncologist. Participants will receive 1 or 2 fractions of SABR, dependent on tumour location, determined by clinical discretion of the treating radiologist. Each SABR treatment will take approximately 1 hour.

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Intervention code [1]2938820

Treatment: Drugs

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Intervention code [2]2938830

Treatment: Devices

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Comparator / control treatment

Nivolumab 240mg every 2 weeks alone (control). Nivolumab is continued until disease progression or prohibitive toxicity.

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Control group

Active

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Outcomes

Primary outcome [1]2973170

Progression free survival (PFS) at 6 months (RECIST 1.1)

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Timepoint [1]2973170

6 months from randomisation

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Secondary outcome [1]3207080

Objective tumour response rate (OTRR, RECIST 1.1)

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Timepoint [1]3207080

1 year and 2 years after randomisation of all planned participants

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Secondary outcome [2]3207090

Adverse events (CTCAE v4.03 and RTOG/EORTC RMSS)

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Timepoint [2]3207090

1 year and 2 years after randomisation of all planned participants

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Secondary outcome [3]3207100

Progression Free Survival (PFS) at 1 year and 2 years. Progression Free Survival will be measured at the interval between the date of randomisation until the date that disease progression is first observed, or the date of death from any cause, whichever occurs first. Disease progression will be determined by a comparing imaging (scans) of documented disease prior to treatment to the first positive scan following study treatment.

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Timepoint [3]3207100

1 year and 2 years after randomisation of all planned participants.

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Secondary outcome [4]3207110

Overall survival (OS) at 1 year and 2 yearsOverall Survival will be measured as the interval from the date of randomisation to the date of death from any cause.

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Timepoint [4]3207110

1 year and 2 years after randomisation of all planned participants.

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Secondary outcome [5]3212360

Tertiary studies aim to identify predictive biomarkers that will allow us to select patients most likely to respond to, and derive benefit from this treatment as well as the presence of other biomarkers whose presence may be indicative of better or worse longer term outcomes such as survival. These may include biomarkers which are often studied amongst patients with non-small cell lung cancer such as PD-L1 expression, EGFR and KRAS mutational status but also novel biomarkers relating to effects of radiation on the immune response.

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Timepoint [5]3212360

Blood samples for translational research, including the identification of biomarkers will be collected on D1, D15 and D29 of study treatment with an additional blood taken within 72 hours of SABR (if D15 bloods do not fall within this 72 hour period). Predictive and prognostic biomarkers will be determined based on patient outcomes such as objective response to treatment based on PD-L1 expression and overall survival.

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Eligibility

Key inclusion criteria

1. Adult (18 years or over) with a histologically or cytologically confirmed diagnosis of NSCLC.2. At least one site of metastasis which is suitable for stereotactic radiotherapy, but for which radiotherapy is not urgently required at the time of enrollment. This must be outside of BOTH the thorax, and the central nervous system, and must not have been previously irradiated. The lesion/s is not required to be measurable or evaluable and must be nominated before randomisation. This lesion will be irradiated in patients randomised to receive radiation.3. At least one lesion (target or non-target according to RECIST 1.1) that is separate and in addition to the lesion nominated for irradiation. This lesion cannot have been irradiated previously.4. Must have relapsed after receiving 1 or 2 lines of chemotherapy for advanced disease including a platinum-based doublet. Maintenance chemotherapy following first line chemotherapy is considered a second line of chemotherapy.5. ECOG performance status of 0 or 1 at the time of randomisation.6. Adequate bone marrow function (done within 14 days prior to randomisation and with values within the ranges specified below). Blood transfusions are permissible.*White blood cell count greater than or equal to 2 x 10^9/L* Absolute neutrophil count greater than or equal to 1.5 x 10^9/L* Platelets greater than or equal to 100 x 10^9/L* Haemoglobin greater than or equal to 90 g/L7. Adequate liver function (done within 14 days prior to randomisation and with values within the ranges specified below):* Alanine transaminase less than or equal to 3 x upper limit of normal (ULN)* Aspartate aminotransferase less than or equal to 3 x ULN* Total bilirubin less than or equal to 1.5 x ULN (except patients with Gilbert Syndrome, who can have total bilirubin less than or equal to x ULN)8. Adequate renal function (done within 14 days prior to randomisation and with values within the ranges as follows: * Serum creatinine less than or equal to 1.5 x ULNor* Creatinine clearance (CrCl) greater than or equal to 40 mL/min (use Cockroft-Gault formula)9. Tumour tissue (formalin-fixed paraffin embedded) must be available for PD-L1 testing. Patients will not be selected by PD-L1 status.10. Willing and able to comply with all study requirements, including treatment, timing and/or nature of required assessments.

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Minimum age

18Years

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Maximum age

No limit

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Gender

Both males and females

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Can healthy volunteers participate?

No

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Key exclusion criteria

1. Active, known or suspected autoimmune disease. Patients are not excluded if they have vitiligo, type 1 diabetes mellitus, residual hypothyroidism due to an autoimmune condition requiring only hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger.2. Any condition requiring systemic treatment with either corticosteroids (greater than 10mg daily prednisone or equivalent dose of an alternative corticosteroid) or other immunosuppressive medications within 14 days of study drug administration. Intranasal, inhaled or topical steroids are permitted in the absence of active autoimmune disease.3. Patients with leptomeningeal or uncontrolled brain metastases are excluded. Controlled brain metastases are those which have been treated and are radiologically and/or clinically stable, and the patient is asymptomatic and does not require corticosteroids.4. Actionable mutation for which an approved, targeted therapeutic is available, e.g. known mutation of epidermal growth factor receptor (EGFR) or translocation of anaplastic lymphoma kinase.5. Chemotherapy in the last 4 weeks.6. Radiotherapy in the last 6 weeks.7. Prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T cell co-stimulation or immune checkpoint pathways.8. Current treatment with other investigational drugs or anti-cancer therapy.9. Life expectancy of less than 3 months.10. History of another malignancy within 3 years prior to randomisation. Patients with a past history of adequately treated carcinoma-in-situ, basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or superficial transitional cell carcinoma of the bladder are eligible. Patients with a history of other malignancies are eligible if they have been continuously disease free for at least 3 years after definitive primary treatment.11. Positive test for hepatitis B virus surface antigen (HBVsAg) or antibodies to hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection.12. History of other significant infection, including HIV. HIV testing not mandatory unless clinically indicated.13. Serious medical or psychiatric conditions that might limit the ability of the patient to comply with the protocol.14. Pregnancy, lactation, or inadequate contraception. Women must be post-menopausal, infertile, or use a reliable means of contraception to avoid pregnancy for 23 weeks after the last dose of nivolumab. Women of childbearing potential must have a negative pregnancy test done within 24 hours prior to randomisation. Men must have been surgically sterilised or use a (double if required) barrier method of contraception if they are sexually active with a woman of child bearing potential for a period of 31 weeks after the last dose of nivolumab.

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Study design

Purpose of the study

Treatment

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Allocation to intervention

Randomised controlled trial

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Procedure for enrolling a subject and allocating the treatment (allocation concealment
procedures)

Patients must meet all eligibility criteria before being randomised.

Randomisation will be performed in an internet based central randomisation system.

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Methods used to generate the sequence in which subjects will be randomised (sequence
generation)

The aim of this study is to determine the activity and safety of treating an asymptomatic, extrathoracic metastasis with a single fraction of SABR, during immunotherapy with nivolumab in advanced NSCLC progressing after 1 or 2 lines of chemotherapy.

Who is it for?Adults with advanced non-small-cell lung cancer (NSCLC) progressing after 1 or 2 lines of chemotherapy and with an asymptomatic, extrathoracic metastasis suitable for SABR. Tumour blocks must be available to test for PD-L1 expression.

Study detailsParticipants will be randomly allocated in a ratio of 2:1 to either nivolumab 240mg every 2 weeks plus SABR (experimental) or nivolumab 240mg every 2 weeks alone (control). Nivolumab is continued until disease progression or prohibitive toxicity.

Participants will be assessed regularly for treatment response and side effects during the treatment and follow up phase. Clinical assessments will be performed before each cycle of nivolumab (2 weekly) and CT scans at baseline, week 6, 12, 18, 24 then 12 weekly until progression. Anticancer treatments and survival will be reviewed every 12 weeks after progression. This will enable us to determine the activity and safety of each treatment option in patients with an asymptomatic, extrathoracic metastasis.